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UBC Theses and Dissertations

Investigating the utility of metabolomics as a tool for predicting graft outcomes in kidney transplant recipients Golan, Or

Abstract

Transplantation has greatly improved the lives of people with end-stage kidney failure, increasing life expectancy by an average of 10 years. However, threats to extended transplant survival continue to pose legitimate concern. Furthermore, the demand for healthy viable organs greatly exceeds supply and ensuring maximal longevity is of utmost importance. Early allograft kidney injury may negatively impact long-term outcomes. Similarly, the emergence of chronic rejection presents a major obstacle for prolonged graft survival and signifies a fundamental failure to achieve stable immune adaptation. Metabolomics focuses on the global measurement of small molecules and is a promising tool in the setting of kidney transplantation. Metabolites reflect ongoing bodily changes occurring at multiple levels —molecule, cell, tissue, organ— and offer a unique perspective that may improve our understanding of the intricate processes involved in graft injury and rejection. This thesis examines metabolite concentrations in the serum before transplantation, and how they may influence immediate and long-term transplant outcomes. To begin, we measured the levels of one individual metabolite (oxythiamine) prior to kidney transplant surgery and tested for association with 1) signs of functional thiamine deficiency early post-transplant; and 2) level of uremia (dialysis adequacy) pre-transplant. Afterwards, we investigated if there are characterizable differences in the pre-transplant serum metabolome of kidney transplant recipients, and whether those differences are associated with chronic rejection outcomes. In the first study, we found that oxythiamine levels are associated with dialysis adequacy at transplant. Patients treated with peritoneal dialysis, who have no residual kidney function and low dialysis adequacy, are particularly vulnerable to manifesting high oxythiamine levels. This subset of patients may be at an increased risk for developing acute thiamine deficiency in the early post-transplant period. In the second study, we were able to demonstrate the presence in serum of innate metabolomic differences between patients, which were associated with chronic rejection outcomes, suggesting that, even before transplantation, the metabolite environment may be an important factor involved in the predisposition of alloimmune differentiation towards a rejection response.

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Attribution-NonCommercial-NoDerivatives 4.0 International